Micelles, mixed micelles, emulsions, micro- and nanoparticles and liposomes, which can consist of different types of raw materials and can be obtained by means of a very wide range of preparation techniques, stand out among colloidal systems proposed for active ingredient transport described in the literature. In any case, the raw materials used in preparing drug release systems will be selected depending on the preferred route of administration and taking into account their approval by the competent authorities.
One material that is common to some of these pharmaceutical carriers are the surface-active substances frequently involved in the processes of preparing same and are incorporated in small amounts.
Only in some cases could surfactants be used as fundamental ingredients of said pharmaceutical carriers. Sorbitan esters are one of these surfactants, and they are of great interest due to their biocompatibility. Sorbitan esters are frequently used in the pharmaceutical industry. The use thereof is due to their properties as lipophilic non-ionic surfactants. Precisely because of this, a person skilled in the art knows that said properties manifest at low surface-active agent concentrations (Owen I. Corrigan and Anne Marie Healy, Surfactants in Pharmaceutical Products and Systems, Encyclopedia of Pharmaceutical Technology, Vol. 14 (Swarbrick, J. and Boylan, J. C., Ed.). Specifically, sorbitan ester concentrations not exceeding 15% are described in the literature (Handbook of Pharmaceutical Excipients, Sixth Edition, Rowe, R. C., Sheskey, P. J. and Weller, P. J (Ed.), Pharmaceutical Press, Chicago, 2009).
In the described context it must be mentioned that there have been authors who have used sorbitan esters as the main component in systems they have developed despite referring to said sorbitan esters as surfactants. The development of millimetric pellet-type systems or of macroscopic gel-type systems, specifically referred to as organogels, for example, could be cited.
In the first case, it is described that the maximum concentration used to obtain pellet-type systems was comprised between 50% for sorbitan monostearate (span 60) and 80% for sorbitan monooleate (span 80) (Podczeck, F., Alessi, P. and Newton, J. M., Int. J. Pharm., 361, 2008, 33-40). Nevertheless, the mentioned authors found that far from developing systems consisting exclusively of said components, the maximum amount of sorbitan ester that could be incorporated into the final systems does not even amount to 23%.
In the second case, macroscopic gels are obtained using high percentages of sorbitan esters (Bari, H., International Journal of Pharmaceutical Sciences Review and Research, Volume 3, Issue 1, July-August 2010; Article 001), (Murdan, Gregoriadis and Florence, International Journal of Pharmaceutics 180 (1999) 211-214) (Murdan, Gregoriadis and Florence, J Pharm Sci., Vol. 88, No. 6, June 1999).
Based on the foregoing, when considering the use of sorbitan esters and referring to them as a surfactant, the person skilled in the art does not consider using them in a high proportion because said proportion would not enable their properties as a surfactant. However, even if the person skilled in the art intends to consider it as a single component or even a majority component of a formulation, it can be inferred from what is described in the literature that only systems having a size greater than micrometers can be developed with such component.
The only systems that could be developed up until now using sorbitan esters as the main component are the following:
A) Microparticulate systems with a mean diameter greater than one micrometer;
B) Microemulsions (LIU Hai-shui, LI Tie-long, JIN Zhao-hui, GONG Yan-zhang, ZHANG Yun-xia, Microemulsion with Span®/Tween as Mixed-surfactant and Synthesis of Iron Nanoparticles, The Chinese Journal of Process Engineering, DOI CNKI-ISSN: 1009-606X.0.2007-01-013) (EP1961412A1);
C) Vesicular reservoir-type nanosystems (e.g. liposomes or niosomes or nanocapsules) as in the case of nanovesicular systems described by Shilpa Kakkar, Indu Pal Kaur in the International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2011.04.027.
Liposomes are colloidal vesicles in which a bilayer membrane structure made up of different types of lipids encloses or encapsulates part of the aqueous phase in which the liposomes themselves are dispersed. The basic unit of the liposomes structure is, therefore, the lipid bilayer forming the vesicular membrane, the formation of which takes place spontaneously in the presence of water. Levels of sophistication in the structure and production method thereof have been incorporated to this spontaneous formation, thus improving the capacity thereof to act like drug release systems and, to the same extent, the possible therapeutic applications thereof. The lipid composition, the particle or vesicle size, the number of lamellae or bilayers forming the wall, as well as the composition of the internal and external aqueous phases or the method of preparation, determine the physicochemical characteristics of the vesicles, their drug encapsulation capacity, and also their stability and behavior both in vivo and in vitro. Liposomes are considered drug carrier systems. However, despite enormous interest, there are significant problems, particularly relating to system stability in body fluids and, particularly, in the bloodstream, where excessive drug loss and rapid interception of the system occurs, with the subsequent removal thereof from circulation, by mononuclear phagocyte system (MPS) cells (Andresen et al., Progress in Lipid Research 44 (2005) 68-97). Such finding represents an obstacle for liposomes as drug carrier systems. It was further found that liposomes generally have a limited encapsulation capacity, especially with respect to hydrophilic drugs, as well as a heterogeneous size, a lack of reproducibility of the prepared formulations often being observed, those characteristics also being related to the methods of preparation thereof (Lian and Ho, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 6, JUNE 2001, 667-680).
The three types of systems mentioned above have a serious problem concerning stability. Vesicular systems and emulsions are known to experience aggregation phenomena, and the difficulty in obtaining more stable formulations by means of processes such as lyophilization without significantly changing their initial characteristics is also known. In this sense, it is important to bear in mind that a considerable energy input and/or the use of specific combinations of surface-active agents is necessary for the formation of such systems, so the obtained product is in an energetically unfavorable situation or unstable. Furthermore, these systems are particularly sensitive to variations in the surrounding area, such as temperature.
On the other hand, microparticulate systems have a certain tendency for sedimentation due to the influence of gravitational force.
As the nanoparticles are matrix-type nanosystems, they are suitable drug release systems because they are more stable than those mentioned above, generally have a greater encapsulation capacity; they can be prepared with a homogenous size.
However, it is not possible to prepare nanoparticles based on sorbitan esters following the teaching of the state of the art, considering nanoparticles consisting of lipophilic components such as solid lipid nanoparticles (SLN) as the closest state of the art (Rainer H. Müller, Karsten Mäder, Sven Gohla, European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 161-177), (S. A. Wissing, O. Kayser, R. H. Advanced Drug Delivery Reviews 56 (2004) 1257-1272).
One of the methods for preparing nanoparticles using excipients having low water-solubility, such as polyesters, is known as emulsification-evaporation, described for example in the scientific article by Gref et al., European Journal of Pharmaceutics and Biopharmaceutics, 51, 2001, 111-118. When the method described in section 2.2 on page 112 is followed, using sorbitan esters as the only component in the organic phase, nanoparticles are not obtained but an aggregate is (see Example 1A of the present specification).
Also, when trying to use another technique such as nanoprecipitation (Paolicelli et al., Nanomedicine, 5, 2010, 843-853), which is frequent in lipid nanoparticle development, it can again be confirmed that a technique with which it is possible to readily obtain nanoparticles based on components having low water-solubility is inefficient for developing nanoparticles with any percentage content by mass of a sorbitan ester (see Example 1B of the present specification).